Simultaneous abuse of cocaine and alcohol is widespread and increasingly detected in patients seeking emergency care. Physiological and behavioral effects of multiple doses of cocaine and alcohol in humans as compared to multiple doses of either drug alone were determined in this double-blind, randomized, within-subjects study using a paradigm more closely approximating practices of drug abusers. Combined administration of cocaine and alcohol produced greater euphoria and increased preception of well-being relative to cocaine. Heart rate was significantly increased following cocaine-alcohol administration. Cocaethylene, detected only following cocaine-alcohol administration, had a longer half-life with increasing plasma concentrations relative to cocaine at later time points. Enhanced psychological effects experienced during cocaine-alcohol abuse may encourage ingestion of larger amounts of these substances over time placing the user at heightened risk for toxic effects, particularly cardiovascular toxicity, than with either drug alone. Future plans include continuation of this study with recruitment of equal number of men and women to obtain a sample size (14 men and 14 women) which will permit an analysis of cocaine and alcohol effects by gender.